I. Field of the Disclosure
Embodiments of this disclosure are directed generally to developmental biology, molecular genetics, and medicine. In particular, the disclosure is directed to the use of isoxazole compounds to promote wound healing.
II. Background
Fibroblasts proliferate in response to biomechanical tension or local stress signals, ultimately differentiating into smooth muscle cell (SMC)-like, contractile myofibroblasts (Eyden 2008, Hinz 2007, Hinz et al., 2001 and Tomasek et al., 2002). Myofibroblast differentiation represents a normal step in the healing process and is essential for the repair of a wide range of traumas including cutaneous injury and myocardial infarction (MI) (Tomasek et al., 2002, Tomasek et al., 2005 and Gurtner et al., 2008). Defective myofibroblast differentiation can result in abnormal or inefficient wound healing while persistent myofibroblast activation is associated with pathological fibrosis and scarring (Wynn 2008). Strategies for modulating myofibroblast number and phenotype may have therapeutic applications for the acute treatment of wounds or fibrosis-associated pathologies, however the molecular mechanisms that regulate these processes are not well understood.
The SMC phenotype is at least partially dependent upon the activity of serum response factor (SRF), which promotes cell growth or differentiation, depending upon association with distinct transcriptional coactivators (Pipes et al., 2006). Interaction with myocardin leads to the activation of genes encoding SMC contractile proteins and the differentiated phenotype (Du et al., 2003, Li et al., 2003, Small et al. 2005, Wang et al., 2001, Hoofnagle et al., 2011 and Huang et al., 2012). Mitogen-activated protein kinase (MAPK) signaling displaces myocardin from SRF by the ternary complex factor (TCF) family of Ets domain proteins, and activation of the immediate early gene response and cell proliferation (Shaw et al., 1989).
While myocardin is specifically expressed in cardiomyocytes and SMCs and is constitutively localized to the nucleus, myocardin-related transcription factor-A (MRTF-A, MKL1, MAL, BSAC) and -B (MRTF-B, MKL2) are broadly expressed and sequestered in the cytoplasm via interactions with G-actin (Pipes et al., 2006, Small et al. 2005, Wang et al., 2001, Cen et al., 2004, Wang et al., 2002 and Olson & Nordheim 2010). Situations of stress that locally alter actin dynamics and promote F-actin polymerization promote nuclear accumulation of MRTFs (Olson & Nordheim 2010, Elberg et al. 2008, Fan et al. 2007 and Zhao et a., 2007). SRF/MRTF complexes bind to consensus CArG elements (CC(A/T)6GG) within the promoters of contractile and SMC-specific target genes (Du et al., 2003, Wang et al., 2002, Olson & Nordheim 2010, Guettler et al., 2008, Miralles et al., 2003 and Kuwahara et al., 2005), most notably smooth muscle α-actin (SMA, ACTA2) and transgelin (TAGLN, SM22) (Sun et al., 2006). MRTFs are thus critical regulators of the smooth muscle contractile phenotype in response to stress.